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Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group

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Abstract

Background and objectives

Rituximab is an anti-CD20 monoclonal antibody approved in the first-line treatment of patients with chronic lymphocytic leukemia (CLL). Rituximab pharmacokinetics shows a time dependency possibly related to changes in the target antigen amount over time. The purpose of this study was to quantify the influence of both CD20 antigenic mass and the FcγRIIIA genetic polymorphism on rituximab pharmacokinetics in CLL.

Methods

Rituximab pharmacokinetics was described in 118 CLL patients using a semi-mechanistic model including a latent target antigen turnover, which allowed the estimation of rituximab target-mediated elimination in addition to the endogenous clearance.

Results

Target-mediated elimination rate constant increased with the baseline CD20 count on circulating B cells (p = 0.00046) and in patients with the FCGR3A-158VV genotype (p = 0.0016). Physiologic elimination of antigen was lower in the Binet C disease stage (p = 0.00018). The effects of these covariates on rituximab concentrations were mainly visible at the beginning of treatment. Body surface area also increased central and peripheral volumes of distribution (p = 1.3 × 10−5 and 0.0015, respectively).

Conclusions

A pharmacokinetic model including target-mediated elimination accurately described rituximab concentrations in CLL and showed that rituximab ‘consumption’ (target-mediated elimination) increases with increasing baseline antigen count on circulating B cells and in FCGR3A-158VV patients.

Clinical trial registration: NCT01370772.

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Acknowledgements

Measurements of rituximab serum concentrations were carried out within the CePiBAc platform. CePiBAc is co-financed by the European Union. Europe is committed to the region center with the European Regional Development Fund. This work was supported by the French Higher Education and Research Ministry under the program ‘Investissements d’avenir’ Grant Agreement: LabEx MAbImprove ANR-10-LABX-53-01. The authors thank Anne-Claire Duveau, Caroline Guerineau-Brochon, and Céline Desvignes for technical assistance. The authors also thank the reviewers for valuable advice, which led to considerable improvement of the manuscript.

Author’s contributions

Mira Tout analyzed and interpreted the data, and wrote the manuscript. Anne-Laure Gagez participated in data interpretation and reviewed the manuscript. Stéphane Leprêtre designed the clinical study, was the principal investigator of the clinical study, and reviewed the manuscript. Valérie Gouilleux-Gruart performed genotyping and reviewed the manuscript. Nicolas Azzopardi participated in data analysis and reviewed the manuscript. Alain Delmer acquired data and reviewed the manuscript. Mélanie Mercier acquired data and reviewed the manuscript. Loic Ysebaert acquired data and reviewed the manuscript. Kamel Laribi acquired data and reviewed the manuscript. Hugo Gonzalez acquired data and reviewed the manuscript. Gilles Paintaud designed the study and reviewed the manuscript. Guillaume Cartron designed the clinical study, was the principal investigator of the clinical study, and reviewed the manuscript. David Ternant designed the study, supervised and participated in the writing of the manuscript, and reviewed the manuscript.

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Authors and Affiliations

  1. Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France

    Mira Tout, Nicolas Azzopardi, Gilles Paintaud & David Ternant

  2. Université de Montpellier, CNRS, UMR 5235, Montpellier, France

    Anne-Laure Gagez & Guillaume Cartron

  3. Department of Hematology, CHU Montpellier, Montpellier, France

    Anne-Laure Gagez & Guillaume Cartron

  4. Department of Hematology, Henri Becquerel Center, Rouen, France

    Stéphane Leprêtre

  5. Laboratory of Immunology, CHU de Tours, Tours, France

    Valérie Gouilleux-Gruart

  6. Department of Hematology, CHU de Reims, Reims, France

    Alain Delmer

  7. Department of Hematology, CHU Angers, Angers, France

    Mélanie Mercier

  8. Department of Hematology, CHU Toulouse, Toulouse, France

    Loïc Ysebaert

  9. Department of Hematology, CHG Le Mans, Le Mans, France

    Kamel Laribi

  10. Department of Hematology, CHG Pontoise, Pontoise, France

    Hugo Gonzalez

  11. Laboratory of Pharmacology-Toxicology, CNRS, UMR 7292, CHU de Tours, 2 boulevard Tonnellé, 37044, Tours Cedex, France

    Gilles Paintaud & David Ternant

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  1. Mira Tout
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  13. David Ternant
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Corresponding author

Correspondence to David Ternant.

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Funding

This study was funded by FILO Group and Roche SAS (Neuilly, France).

Conflict of interest

Mira Tout, Anne-Laure Gagez, Stéphane Leprêtre, Valérie Gouilleux-Gruart, Nicolas Azzopardi, Alain Delmer, Mélanie Mercier, Loic Ysebaert, Kamel Laribi, and Hugo Gonzalez have no conflicts of interest to declare. Gilles Paintaud reports grants received by his research team from Novartis, Roche Pharma, Genzyme, MSD, Chugai, and Pfizer. Guillaume Cartron received consultancy fees from Roche and Celgene, honorarium from Roche, Celgene, Jansen, Gilead, and Sanofi, and travel arrangement from Jansen, Gilead, and Sanofi. David Ternant has given lectures for Sanofi and Amgen.

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Tout, M., Gagez, AL., Leprêtre, S. et al. Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group. Clin Pharmacokinet 56, 635–647 (2017). https://doi.org/10.1007/s40262-016-0470-8

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